3,3-disubstituted-3,4-dihydrobenzodioxepins

ABSTRACT

3-Hydroxy-3-(substituted-aminoalkyl)-3,4-dihydro-2H-1,5benzodioxepin products are described that exhibit Beta adrenergic stimulating properties and are therefore suitable for use as broncho-dilating agents. The products are prepared essentially by four principal routes from 3-oxo-3,4-dihydro-2H1,5-benzodioxepins. By one route the 3-oxobenzodioxepin is treated with a nitroalkane to give a 3-hydroxy-3-nitroalkylbenzodioxepin the nitro group of which is reduced to an amine and the resulting compound reacted with an aldehyde or ketone under hydrogenating conditions to introduce the desired substituent into the amino function. By a second route the 3-oxobenzodioxepin is reacted with an alkali metal nitrile to form the cyanhydrin which upon reduction forms the 3-hydroxy-3-aminoalkylbenzodioxepin that can be treated with a ketone or aldehyde to give the desired products or can be reacted with sodium nitrite or other agent to form a 3-spiro-benzodioxepin-2&#39;&#39;-oxirane which upon reaction with an amine provides the desired product. The 3spiro-benzodioxepin-2&#39;&#39;-oxirane also can be obtained by treatment of the 3-oxo-benzodioxepin with a sulfurylide. A fourth method involves forming a benzodioxepin-3-spiro-5&#39;&#39;-oxazolidin-2&#39;&#39;-one which upon treatment with dilute alkali gives the desired 3hydroxy-3-(substituted aminoalkyl)-3,4-dihydro-2H-1,5benzodioxepin. The intermediate oxazolidinone compounds can be treated if desired with various agents to attach substituents on the benzenoid moiety of the starting substance. These oxazolidinones exhibit Beta -stimulating and skeletal muscle relaxant properties.

United States Patent Wasson et al.

[54] 3,3-DISUBSTITUTED-3,4-

DIHYDROBENZODIOXEPINS [72] Inventors: Burton K. Wasson, 103 Broadview,

Valois, Quebec; Haydn W. R. Williams, 348 Barberry Place, Dollard desOrmeaux, Quebec, both of Canada [73] Assignee: Charles E. Frosst 8: Co.,Montreal,

Quebec, Canada [22] Filed: June 9, 1969 [21] Appl. No.: 832,879

Related U.S. Application Data [63] Continuation-impart of Ser. No.755,442, Aug.

26, 1968, abandoned.

[52] U.S. Cl. ..260/340.3, 260/247.2, 260/268, 260/296, 260/306.7,260/306.8, 260/307, 260/326.15, 260/340.5, 424/278 4/ 1966 Augstein etal. ....260/340.3 X

Primary ExaminerAlex Maze] Assistant Examiner-James H. TurnipseedAttorneys- Erma R. Coutts, Harry E. Westlake, Jr. and J. Louis Welk.

45 Oct. 24, 1972 I ABSTRACT3-Hydroxy-3-(substituted-aminoalkyl)-3,4-dihydro- 2H-l,5-benzodioxepinproducts are described that exhibit B-adrenergic stimulating propertiesand are therefore suitable for use as broncho-dilating agents. Theproducts are prepared essentially by four principal routes from3-oxo-3,4-dihydro-2l-l-l ,5- benzodioxepins. By one route the3-oxobenzodioxepin is treated with a nitroalkane to give a 3-hydroxy-3-nitroalkyl-benzodioxepin the nitro group of which is reduced to an amineand the resulting compound reacted with an aldehyde or ketone underhydrogenating conditions to introduce the desired substituent into theamino function. By a second route the 3-oxobenzodioxepin is reacted withan alkali metal nitrile to form the cyanhydrin which upon reductionforms the 3-hydroxy-3-aminoalkyl-benzodioxepin that can be treated witha ketone or aldehyde to give the desired products or can be reacted withsodium nitrite or other agent to form a 3-spiro-benzodioxepin-2'-oxiranewhich upon reaction with an amine provides the desired product. The3-spiro-benzodioxepin-2'-oxirane also can be obtained by treatment ofthe 3-oxobenzodioxepin with a sulfurylide. A fourth method involvesforming a benzodioxepin-3-spiro-5 -oxazolidin- 2-one which upontreatment with dilute alkali gives the desired 3-hydroxy-3-(substitutedaminoalkyl)-3,4- dihydro-ZH-l,S-benzodioxepin. The intermediateoxazolidinone compounds can be treated if desired with various agents toattach substituents on the benzenoid moiety of the starting substance.These oxazolidinones exhibit B-stimulating and skeletal muscle relaxantproperties.

23 Claims, N0 Drawings 1: 3,3-DISUBS'I'ITUTED-3,4- DIHYDROBENZODIOXEPINSThis application is a continuation-in-part of our US. Pat. application,Ser. No. 755,442, filed Aug. 26, 1968, now abandoned.

This invention is concerned with 3,3-disubstituted benzodioxepins whichexhibit B-adrenergic stimulating properties which make them uniquelysuitable forruse as broncho-dilating agents.-

The novel 3,3-disubstituted benzodioxepins of this invention can beillustrated by the structural formula and pharmacologically acceptablesalts thereof wherein R is selected from hydrogen, hydroxy, lower alkyl(C and lower alkoxy (C R is selected from hydrogen, halogen particularlychloro and bromo, lower alkyl (C, nitro, amino, mono-or di-loweralkylamino, acylamino wherein the acyl radical is the residue of analkyl (C sulfonic acid or an alkyl (C carboxylic acid, lowercarboalkoxyamino, hydroxy or lower alkoxy (C X and X are selected fromhydrogen, lower alkyl (C and halogen; R and R can be the same ordissimilar and are each separately selected from hydrogen, lower alkyl(C phenyl or phenyl-lower alkyl (C lower cycloalkyl, pyridyl andpyridyl-lower alkyl (C R is selected from hydrogen and lower alkyl (Cand the grouping -NR R represents the amino group or a monoordi-substituted amino group or a nitrogen containing heterocycliogroupand in particular an NR R group where R representshydrogen; lower alkyl(-C,. and sub stituted lower alkyl such as 2-phenyl-2-hydroxyethyl,

and R represents (1) lower alkyl having aclvantageously from one to 10carbon atoms and being either straight or branched chain, and beingeither unsubstituted or substituted with one or more groups selectedfrom (a) amino or monoor di-loweralkyl (C amino, or the aminosubstituent canbe wherein R, R" and X have -the above assignedmeanings,- (b) cycloalkyl having from three to six carbon atoms, (c)lower alkoxy having from one to three carbon atoms,-'(d) hydroxysubstituted lower alkoxy havingfrom one to three carbon atoms,;(e)hydroxy, (f) phenyl or mono-or poly-substituted phenyl wherein thesubstituents are selected from halo especially chloro or bromo, hydroxyand lower alkoxy (C or.

wherein the substituted phenyl is the 3,4- methylenedioxyphenyL-l g) aheterocyclic substituent such as an indolyl, morpholino or :1,2,5-thiadiazolyloxy, (2) acycloaliphatic. such as a cycloalkyl havingfrom three to l 0 carbon atoms such'as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, tricyclodecane such as adamantyl and the like,or a phenyl-lowercycloalkyl as phenyl-cyclohexyl, (3) lower alkenylhaving from three to five carbon atoms, (4) lower alkynyl having fromthree to five carbon atoms, (5) phenyl or substituted phenyl wherein themonoor poly-substituents are selected from a halogen such as chloro andbromo, lower alkyl (C and lower alkoxy (C (6) a heterocyclic substituentsuch as 2 -pyridyl, (7) the residue of a guanidine moietyv of thestructure NH (|L,-NHR7 wherein R is hydrogen, lower alkyl, benzyl orphenyl or substituted phenyl wherein the substituent is one or moregroups selected from halo, especially chloro or bromo, lower alkyl (C orlower alkoxy (C (8) the benzodioxepin radical v wherein R, R and X havethe above assigned meanings, but preferably they represent hydrogen; andin addition the grouping NR"R can represent a morpholino, piperazinyl,N-phenyl-piperazinyl, aziridinyl or 3-( 2-iminothiazolidinyl) group.

The novel 3,3-disubstituted benzodioxepins of this inventionadvantageously are prepared by the reactions illustrated in Flow Diagram1.

According to the above reaction scheme it is seen that the desired3,4-dihydro-2H-l,5-benzodioxepin, product 1, is obtained fromthe 3-ketocompound. A by one of two methods depending upon whether R is hydrogenor whether it represents a lower alkyl group of from one to fourcarbons. Additionally, the 3-keto compound A" can be directlyconverted-tothe 3- spiro-2 -oxirane E by use of a sulfur ylide.

When R is hydrogen, the 3-keto intermediate A? in an acidic solvent iscaused to react with aqueous hydrogen cyanide, conveniently generated insitufrom sodium or potassium cyanide to provide the 3-hydroxy- 3-cyanointermediate C which is separated and reduced to provide the3-hydroxy-3-aminoalkyl intermediate D. Treatment of intermediate D withacetone orother ketone or aldehyde that will yield the group R uponreduction provides the desired product:

1. Intermediate fD. also can be treated with an alkali nitrite to formthe.3-spiro-2'-oxirane E which when reacted with the desired amine formsproduct I, I

The first step of the above procedure,zthat is treatment of the 3-ketocompound A with aqueous alkali cyanide, advantageously is carried'out inthe presence of acetic anhydride or other acidic solvent, e.g.,' aceticacid or alternatively with anhydrous hydrogen cyanide.

The reduction of intermediate'C can be either a catalytic or chemicalreduction; catalytic reduction desired 'chemicaI reduction can be'efi'ected with a metal '-hydride advantageously lithium aluminumhydrideor other metal hydridels, "preferably in diethyl ether ortetrahydrofur an; Each method affords good yields of product D". IIntermediate" D.- then desired 3,3-disubstituted benzodioxepin I of thisinvention by either of two routes. One of the routes employed forpreparing product "I wherein R is hydrogen, involves the reaction ofintermediate D with a ketone or aldehyde that will yield the group R andsubsequent reduction advantageously can'ied out byhydrogenation in thepresence of a transition metal catalyst in an organic solvent such a aloweralkanol as ethanol, propanol, butanol or isomers thereof and thelike, employing vacidic conditions when required or chemical-reductionwith sodium borohydride can be employed.

The second more general method for preparing product I. where R and Rhave the meaning given above involves the reaction of intermediate Dwith I an alkyl nitrite or with nitrous acid generated in situ from analkali metal nitrite (sodium or potassium nitrite being quite suitable)advantageously carried out:

with cooling to provide a 3-spiro- 2'-oxirane "E" as well as the3-hydroxy-3-hydroxy-methyl analog. The novel 3-hydroity-3-hydroxymethylproducts also exhibit can be convertedto the I Sulfur ylide anotherfeature of this invention. The mar-mirane E" obtained then, is reactedwith the amine, l-INR-"R, advantageously in the presence of an organicsolvent such as a lower alkanol at ambient temperature to give thel.\Vhen R represents the amidine group. a

theseproductsalsocanbepreparedbyreactionof product I, wherein R and Rrepresent hydrogen with an S-loweralkylisothiuror'lium salt. of thestructure compounds can be prepared by the methods described adrene'rgicstimulating properties, and constitute I above or by initially treatinga 3-hydroxy-3-(R'NH- 10ml I 0202 CH )-benzodioxepin with phosgene in thepresence of a base. Phosgene advantageously in admixture with chloroformis added dropwise with stirring to a cooled solution of thebenzodioxepin in the same solvent. The 3-spiro-5'-oxazolidin-2-oneobtained is admixed with acetic acid, cooled to the freezing point andtreated dropwise with a mixture of nitric acid and sulfuric acid toprovide the corresponding 7-nitro-3-spiro-5-oxazolidin-2-one compoundwhich in the presence of dilute alkali, as aqueous sodium or potassiumhydroxide, gives the desired 7-nitro-3-hydroxy-3-(R NHCl-l)benzodioxepin, l-a.

Catalytic reduction of l-a or its intermediate 7-nitro-3-spiro-5'-oxazolidin-2-one, advantageously with palladium or RaneyNickel, provides the corresponding 7- arnino derivative. The7-amino-3-spiro-5'-oxazolidin-2' -one when treated with aqueous alkaligives the 7- amino-3-hydroxy-3-(R NHCH )benzodioxepin, I-b.

Product l-a also can be converted to the 7-amino analog, l-b, or to the7-lower acylamino by first reacting I-a with an aldehyde YCHO, wherein Ycan be lower alkyl, phenyl or the residue of any commercially availablealiphatic or aromatic aldehyde,'to form the 7-nitro-2'-Y-3-spiro-5-oxazolidine which, upon reduction as describedabove, gives the corresponding 7- amino compound which can either betreated with aqueous alkali to provide product l-b or treated with alower alkyl sulfonyl halide or a lower alkanoyl halide to give thecorresponding 7-acylamino-2'-Y-3-spiro-5'- oxazolidine which whentreated with acid, especially with a mineral acid or strong organicacid, gives the 7- acylamino-3-hydroxy-3-(RNHCl-l )benzodioxepin, I-c.

Diazotization of the 7-amino-3-spiro-5'-oxazolidin- 2'-one, prepared asdescribed above, gives the corresponding 7-hydroxy compound which, inthe presence of base, such as barium hydroxide gives 3,7- dihydroxy-3-(RNHCHQbenzodioxepin, ld.

The 6- and/or 7-hydroxy-benzodioxepins, I, also can be prepared from thecorresponding 6- and/or 7-alkoxy-benzodioxepins by treatment with strongmineral acid.

The 3-spiro-2'-oxirane E can also be prepared by treatment of the 3-ketocompound A with either dimethyloxosulfonium methylide ordirnethylsulfonium methylide either with cooling or at a temperature upto ambient temperature. In practice, the dimethyloxosulfonium methylideis prepared under nitrogen from sodium hydride, trimethyloxosulfoniumiodide and dimethyl sulfoxide. The ketone, A, is added slowly to themixture at ambient temperature and the mixture stirred for about 24hours. The dirnethylsulfonium methylide advantageously is prepared frombutyl lithium and trimethylsulfonium iodide in tetrahydrofuran. Theketone A then is added and the reaction mixture held at 0 C. for 1 hourand then for a short period at ambient temperature. Isolation in eachinstance provides the desired 3-spiro-2' -oxirane, E.

.To prepare the products wherein R is a lower alkyl group, the ketone Ainitially is reached with a nitroalkane to give intermediate B whichupon reduction provides intermediate D. The reaction of the ketone Awith the nitro-alkane advantageously is carried out in ethanol or otherlower alkanol or ether in the presence of sodium ethoxide or otheralkali metal alkoxide to give a salt of B from which the com- 56m isliberated by treatment with a weak acid such as acetic acid. Thereduction of intermediate B to form D is effected advantageously inethanol (or other lower alkanol)-acetic acid with hydrogen and RaneyNickel or palladium.

While the unsubstituted 3-keto compound A is known, it was obtained inlow yields as a by-product in the preparation ofl,4-benzodioxane-3-carboxylic acid. All attempts by these investigatorsto prepare the 3- keto-benzodioxepin either failed or provided verysmall yields of the desired product. A process thus had to be devisedfor the preparation of this ketone which has been found to give veryhigh yields of compound A. This novel synthetic route for thepreparation of the 3- keto compound A can be illustrated as shown in oDears l1- A According to the reaction scheme illustrated in Flow Diagram1], the catechol starting material E is converted to the 3-keto productA by initial reaction with a haloalkanonitrile or a haloalkanoic acidester.

Treatment of the catechol E with a haloacetonitrile of the structure XCRR CN, to afford the l,2-bis-(cyanoalkoxy)-benzene, F is carried out inone step when R and R each represent hydrogen, however, when it isdesired to form product F wherein R and R are other than hydrogen, thenthe catechol (R=R=H) initially is treated with one equivalent ofhalo-acetonitrile, the orthocyanomethoxyphenol isolated and then reactedwith the haloalkanonitrile to give F wherein R and/or R are other thanhydrogen.

When R or R is other than hydrogen then it is preferred to use theappropriately substituted salicylaldehyde which is treated with theappropriate haloalkanonitrile, and the resulting compound oxidized byperacetic acid followed by mild hydrolysis to give theorthocycano-alkoxyphenol which then is treated with haloacetonitrile toprovide F. Product F then is cyclized by treatment with a mixture ofsodamide and a solvent selected preferably from dimethyl sulfoxide(DMSO), dimethylformamide (DMF), sulfolane, benezene, toluene or xyleneor by treatment with an alkali metal tert.-butoxide or other alkalimetal, t.-alkanolate in DMSO, DMF, benzene, toluene, xylene, sulfolaneor a t.-alkanol corresponding to the alkanolate employed, or bytreatment with sodium or potassium lower alkanolate, sodium hydride,potassium-sodium amalgam (1:1) lithio or sodio-N-methylaniline, to formthe 3-amino-4-cyano-2l-l -l ,5 -benzodioxepin, G Best results areobtained when this step is carriedgut in an inert atmosphere such asunder nitrogen or other inert gas such as argon or other usual inertgas. Intermediate G is hydrolyzed and decarboxylated to the ketone Aeither by first refluxing in aqueous acetic acid followed by refluxingwith phosphoric acid, or by acid alcoholysis followed by heating inaqueous alkanol to effect hydrolysis and decarboxylation. Whileintermediate G is illustrated as having the structure 3-amino-4-cyano,its tautomer, 3-imino-4-cyano-3,4- dihydro-ZH-l,S-benzodioxepin may alsobe present. It is understood that when X, X, R and/or R is/are otherthan hydrogen, additional isomers are possible. However, upon hydrolysiswith concomitant decarboxylation by either of the above procedures alltautomers or isomers are converted to the 3-keto compound A. Step A:Preparation of l,2-bis-carbomethoxymethoxybenzene (or l,2-benzene-bismethyl glycolate) FLOW DIAGRAM II X X X .li. /R I I R /R )(l or -(;NR2R3 CN X --OII Y CR3RL C ogAlk X O-CCO2Alk lt )UCII2CN R OH R-O-CH2CO2A1k I l t R R l Cyclization lcyclization agent agent X R R: R R

| 04/ l o X NH2 *0 R R O R N COzAlk hydrolysis 9N hydrolysis anddecarboxylation decarboxylation The' second of the principal methods formaking compound A from the catechol E involves initial reaction of Ewith a halo-alkanoic acid ester, halo- CR'R--CO,alkyl, to give the1,2-bis-alkoxycarbonylalkoxybenzene, F When R and R in compound Fareeach hydrogen, compound F is produced in one step. When R and/or R areother than hydrogen, then the catechol (X=X'=R=R =H) initially istreated with haloacetic acid ester, theortho-alkoxycarbonylmethoxyphenol isolated and then reacted with ahaloalkanoic acid ester to give F wherein R and/or R are other thanhydrogen. When X, X, R and/or R is/are other than hydrogen, preferablythe appropriate 'salicylaldehyde is reacted with Z- ,CRRCOalkyl whereinR and/or R is other than hydrogen and the resulting compound oxidized byperacetic acid followed by mild hydrolysis to give theortho-alkoxycarbonylalkoxyphenol or the corresponding acid which can bereesterified. The ester then is treated with an alkyl haloacetate toprovide intermediate F. Cyclization of compound F to form G is effectedby substantially the same method described above for the cyclization ofF to provide G. Hydrolysis and decarboxylation of G by acid hydrolysisin a lower alkanol advantageously by employing aqueous hydrochloric acidin methanol or ethanol followed by heating gives the desired 3-ketocompound A".

The pharmacologically acceptable salts of the benzodioxepins of thisinvention are prepared by the reaction of product I with an inorganic ororganic acid such as hydrochloric, hydrobromic, sulfuric, phosphoric,formic, acetic, succinic, lactic, malic, tartaric, citric,

maleic, phenylacetic, benzoic, salicyclic, or ptoluenesulfonic acid orsimilar acids that are known to provide pharmacologically acceptablesalts.

The benzodioxepins however can be employed in pharmaceuticalformulations either in the form of free bases or in the form of theiracid addition salts in conjunction or admixture with organic orinorganic solid or liquid pharmaceutical excipients. Thesepharmaceutical formulations can be in the form of tablets, solutions,suspensions, emulsions, or aerosols suitable for oral or topicaladministration.

Unlike hitherto known bronchodilators which generally are short acting,the benzodioxepin products of this invention exhibit a long duration ofactivity. The compounds were found when tested according to accepted dtatt 1 9la 9t9tqy preqssiqrs i guinea pigs to be orally effective withina dosage range o fFoTn about 1 mg. to about 20 mg./kg. and whenadministered intravenously the effective dosage range was betweenmicrog./kg. to 2 mg./kg. At these dosages the products were acceptablytolerated by the animals.

The 3 '-R -6-R-7-R-3,4-dihydro-2I-l-l ,S-benzodioxepin-3-spiro-5-oxazo1idin-2'-one compounds prepared in the synthesis of the principalproducts of this invention, are also novel and form another feature ofthis invention. In addition to exhibiting bronchodilating properties,these compounds also exhibit muscle relaxing properties and aretherefore useful in the relief of spastic states.

The following examples will illustrate the preparation of representativeproducts of this invention prepared by the above-described procedures.It will be understood that while all of the compounds can be prepared bythe procedure described in the following examples, modifications of theprocedural steps which would be obvious to the skilled chemist can beemployed. The following examples therefore are not to be considered aslimiting the preparation of any particular compound to the preciseprocedural steps described in the examples which are provided solely toillustrate the best mode currently known to applicant.

Where the term benzodioxepin is employed in the disclosure and claims itis to be understood to mean 3 ,4-dihydro-2H-l ,S-benzodioxepin.

The following examples describe the preparation of the novel products ofthis invention by the route A C D" I illustrated in Flow Diagram 1.

EXAMPLE 1 3-l-lydroxy-3-isopropylaminomethyl-3 ,4-dihydro-2H-1,5-benzodioxepin Hydrochloride Step A: Preparation of 1,2-di-(cyanomethoxy)benzene A mixture of 99 g. (0.9 moles) of catechol, 90.6 g.(1.2 moles) of chloroacetonitrile, 168 g. (1.22 moles) of finelypowdered potassium carbonate, and 600 ml. of acetone is refluxed withstirring for one and one-half hours. The mixture then is treated with45.3 g. (0.6 mole) of chloroacetonitrile and 84 g. (0.608 mole) ofpotassium carbonate, and refluxed for a further 3.5 hours. The mixtureis filtered, the solids washed with 150 ml. of acetone and the combinedfiltrate evaporated in vacuo to give an oil. The oil which crystallizesis recrystallized from ethanol-water (8: 1) to give 138 g. (81.5%) of 1,2-di-(cyanomethoxy)benzene,

m.p. 85.086.5 C. Further recrystallization from the same solvent systemaffords the product melting at 85.0-85.5 C.

Analysis calculated for C 11 14 0 C, 63.82; H, 4.29; N, 14.89;

Found: C, 64.17; H, 4.48; N, 14.94. Step B: Preparation of3-arnino-4-cyano-2H-l,5- benzodioxepin Sodamide (49.2 g., 1.26 mole) isadded with stirring under nitrogen to 370 ml. of dry dimethyl sulfoxide.After the initial vigorous evolution of ammonia has subsided thesolution is heated one-half hour at 60 C. A solution of 115.8 g. (0.616mole) of 1,2-di- (cyanomethoxy)benzene in 246 ml. of dimethyl sulfoxideis added with stirring and cooling (water bath at ambient temperature)during one hour and the reaction mixture stirred for a further two hoursat ambient temperature. A mixture of 81.5 ml. of acetic acid and 246 ml.of water is added slowly accompanied by stirring and cooling. Themixture is poured into 1.2 liters of water and the tan-colored solidscollected. The solids are recrystallized from chloroform to give 75.5 g.(65%) of 3-amino- 4-cyano-2H-l,S-benzodioxepin, m.p. 167l69 C. Furtherrecrystallization from chloroform affords the product melting at l68169C.

Analysis calculated for C H N 0 C, 63.82; H, 4.29; N, 14.89;

Found: C, 63.80; H, 4.35; N, 14.70.

benzodioxepin can be prepared as follows.

A solution of 9.4 g. (50 millimoles) of 1,2-di- (cyanomethoxy)benzene in20 ml. of dimethyl sulfoxide is added under nitrogen to a stirredmixture of 12.3 g. millimoles) of potassium tert.-butoxide in 30 ml. ofdimethyl sulfoxide cooled in a water bath at ambient temperature. Themildly exothermic reaction raises the internal temperature of themixture to 42 C. The mixture is stirred a further 2 hours and a solutionof 6.6 ml. of acetic acid in 20 ml. of water added slowly with cooling.[Altematively, the reaction mixture can be poured into the aqueousacetic acid solution] The product is precipitated by pouring the mixtureinto 100 ml. of water. The beige-colored solid is collected, washed withwater, and air dried to give 9.5 g. of crude product, m.p. 148-154 C.The crude product is recrystallized from 200 ml. of chloroform to afford5.8 g. (61.7%) of 3-amino-4-cyano-2H-l,S-benzodioxepin. A mixed meltingpoint with the product obtained above gave no depression.

Step C: Preparation of 3-oxo-3,4-dihydro-2H-l,5- benzodioxepin A mixtureof 16.0 g. (85.1 millimoles) of 3-amino-4- cyano-ZH-1,5-benzodioxepin,18 ml. of water, and 300 ml. of acetic acid is refluxed one-half hour.The mixture is treated dropwise with ml. 85% phosphoric acid and thenrefluxed overnight. The solution is cooled to ambient temperature, andpoured onto 500 g. of crushed ice. Ammonium sulfate g.) is added and thesolution continuously extracted with ether for several hours. Theethereal solution is evaporated to dryness to remove ether and aceticacid, and the residual oil dissolved in diethyl ether, washed with 10%sodium carbonate solution, dried, and evaporated. The resulting oil isfractionated to give 8.96 g. (64%) of 3-oxo-3,4-dihydro-2Hl,5-benzodioxepin, b.p. 52-6l C. at 0.07 mm pressure,which at first is a colorless oil which solidifies. The product is useddirectly in the next step. 1

Step D: Preparation of 3-hydroxy-3-cyano-3,4-dihydro- 2H- l,S-benzodioxepin A solution of l3.5 g (208 millimoles) of potassiumcyanide in 27 ml. of water is added dropwise to a mixture of 18.7 g.(114 millimoles) of 3-oxo-3,4-dihydro-2 H-l,5-benzodioxepin and 21.2 g.(208 millimoles) of acetic anhydride with stirring and cooling. Themixture is stirred at ambient temperature overnight and then is madealkaline with sodium carbonate solution. The product in the form of anoil is extracted with diethyl ether, treated with charcoal and driedover calcium sulfate. Evaporation of the solvent gives a solid thatisrecrystallized from carbon tetrachloride to give3-hydroxy-3-cyano-3,4-dihydro-2H- l ,S-benzodioxepin as plates, m.p.l08.5l 10 C.

Analysis calculated for C H NO C, 62.82; H, 4.74; N, 7.33;

Found: C, 62.70; H, 4.52; N, 7.09.

An alternative method for preparing 3-hydroxy-3-cyano-3,4'-dihydro-2H-l,5-benzodioxepin can be carried out in thefollowing manner.

To a stirred solution of 4.92 g. (30 millimoles) of 3-oxo-3,4-dihydro-2H-l,S-benzodioxepin in 100 ml. of benzene is addeddropwise a solution of 30 millimoles of anhydrous hydrogen cyanide in 50ml. of benzene. The reaction mixture is stirred overnight at ambienttemperature, basified with 10% sodium carbonate solution and the organiclayer separated. The benzene solution is washed once with water anddried successively over anhydrous magnesium sulfate and calcium sulfate.Evaporation of the solvent under reduced pressure at 40 C. yields thecrude cyanohydrin which upon purification and mixed melting pointdetermination gives no depression with an authentic sample of3-hydroxy-3- cyano-3,4-dihydro-2H- 1 ,S-benzodioxepin.

Step E: Preparation of 3-hydroxy-3-aminomethyl-3,4- dihydro-2H- l,5-benzodioxepin hydrochloride A mixture of 9.5 g. (49.7 millimoles) of3-hydroxy-3- cyano-3,4-dihydro-2H-l ,5-ben'zodioxepin, 75 ml. ofanhydrous ethanol, and 3 ml. of acetic acid is shaken under hydrogen atambient temperature and pressure in the presence of 100 mg. of platinumoxide and a little ethanolic-hydrogen chloride. The catalyst is removedand the filtrate evaporated to dryness to give 5.2 g. of crude product,m.p. 207-214 C. Recrystallization of this crude product from isopropanolafford 3-hydroxy- 3-aminomethyl-3,4-dihydro-2H- l ,S-benzodioxepinhydrochloride, m.p. 228230 C. (clearing at 238 C.)

Analysis calculated for c,,H,,No,-Hc1;

C, 51.84; H, 6.09; N, 6.06;

Found: C, 52.1 1; H, 6.13; N, 5.86.

An alternative method for preparing 3-hydroxy-3-amino-methyl-3,4-dihydro-2H- l ,S-benzodioxepin can be carried out inthe following manner.

3-Hydroxy-3-cyano-3 ,4-dihydro-2H- 1 ,5-benzodioxepin (30 millimoles) isdissolved in 100 ml; of dry diethyl ether and the solution addeddropwise during a period of 0.75 hours under dry nitrogen to a stirredslurry of 3.8 g. (100 millimoles) of lithium aluminum hydride in 100 ml.of dry ether. The mixture is stirred under reflux for 2.25 hours andtreated carefully with 3.8 ml. of water. An easily filterableprecipitate of metallic compounds is obtained by the dropwise additionof 5.7 ml. of 10% sodium hydroxide solution followed by l 1.4 ml. ofwater. The ethereal solution is filtered and the filter-cake then iswashed with 50 ml. of diethyl ether. The combined filtrate is dried overanhydrous magnesium sulfate and again over calcium sulfate beforeevaporation in a rotary film-evaporator to yield 5.13 g. (87%) of thefree base as a colorless solid, mp. 60-63 C. (to a turbid melt). Thisproduct, upon recrystallization from benzene from which it separates ascolorless plates melts at 66-68 C. A solution of 3.0 g. of the basedissolved in dry diethyl ether is treated with a slight excess ofapproximately 5N ethanolic-hydrogen chloride solution affording 2.82 g.of 3-hydroxy-3aminomethyl-3,4-dihydro-2H-1,5- benzodioxepinhydrochloride. This product gives no depression in melting point whenadmixed with authentic material prepared by the catalytic reduction ofthe cyanohydrin, as described above.

Step F: Preparation of 3hydroxy-3- isopropylaminomethyl-3,4-dihydro-2H-l ,5-benzodioxepin Hydrochloride A mixture of 3.92 g.(16.95 millimoles) of 3-hydroxy-3-aminomethyl-3,4-dihydro-2H- 1,S-benzodioxepin hydrochloride, 1.39 g. 16.95 millimoles) of anhydroussodium acetate, and ml. of anhydrous ethanol is stirred under nitrogenfor twenty minutes. Acetone (1.08 g., 18.6 millimoles) is added and themixture stirred for 30 minutes. The mixture is hydrogenated at ambienttemperature and pressure for 1% hours over mg. of platinum oxide. Thecatalyst is removed, the solution evaporated to a syrup, 60 ml. of drydiethyl ether added, and a slight excess of 9.7N ethanolichydrogenchloride solution added. The solids are collected to give 4.65 g. ofcrude product, m.p. 172175 C. The product is recrystallized fromisopropanol to give 3.05 g. (65%) of 3-hydroxy-3- isopropylaminomethyl-3,4-dihydro-2H-l ,S-benzodioxepin hydrochloride, m.p. l78.5-180.0 C.

Analysis calculated for C H NO 'HCl:

C, 57.04; H, 7.36; N, 5.11;

Found: C, 56.95; H, 7.29; N, 4.89.

An alternative method for preparing the benzodioxepin of Step F can becarried out in the following manner.

3-Hydroxy-3-aminomethyl-3 ,4-dihydro-2H- 1 ,5- benzodioxepin mg., lmillimole) is dissolved in isopropanol (3 ml.) and treated with acetone(64 mg., 1.1 millimoles). On standing overnight, the solution deposits acrystalline solid (glistening plates), and this is reduced in situ bythe addition of sodium borohydride (75.6 mg., 2 millimoles). Afterstirring the mixture at ambient temperature for 3 hours water (20 ml.)is added and then 2.75N hydrochloric acid (1.5 ml.). The solution isextracted with ether (10 ml.) and the extract rejected. Glycerol (1 ml.)is added and the solution then is basified with 2N sodium hydroxide (5ml.) to liberate the free base. The latter is extracted with ether (25ml.), the ethereal solution washed with water (2 X 10 ml.) and thendried thoroughly over magnesium sulphate followed by calcium sulphate.Addition of 5N ethanolic hydrogen chloride solution to the solution ofbase precipitated the 3-hydroxy-3- isopropylaminomethyl-3,4-dihydro-2H-1,S-benzodioxepin hydrochloride 136 mg., 49.6%). No depression of meltingpoint is observed when the product is admixed with an authentic specimengfgecompound.

EXAMPLE 2 3-Hydroxy-3-guanidinomethyl-3,4-dihydro-2H-l ,5 benzodioxepinSulfate 3-Hydroxy-3-aminomethyl-3,4-dihydro-2H- l ,5- bcnzodioxcpin fromExample 1, Step E, (1.95 g., l millimoles) and 2.78 g. 10 millimoles) ofS- methylisothiourea sulfate in 15 mls. of dimethylformamide and 2 mls.of water is heated at 90l00 C. for hours. The solvent is evaporated invacuo and the residue recrystallized from ethanol to give 3-hydroxy-3-guanidinomethyl-3,4-dihydro-2H- l ,5 -benzodioxepin sulfate.

EXANIPLE 3 3-Hydroxy-3-( 3-phenylguanidinomethyl )-3 ,4-dihyd ro- 2H- 1,5 -benzodioxepin I-Iydriodide A mixture of S-methyl-N-phenylisothioureahydriodide (2.94 g., millimoles), 3-hydroxy-3-aminomethyl-3,4-dihydro-2H-l ,S-benzodioxepin 1 .95 g. (10 millimoles)from Example 1, Step E, and 20 mls. of ethanol is warmed until evolutionof methyl mercaptan ceases and then is refluxed for two hours. Thesolution then is evaporated to a small volume and diluted with ether togive 3-hydroxy-3-(3-phenylguanidinyl)- methyl-3,4-dihydro-2I-l-l,5-benzodioxepin hydriodide.

EXAMPLE 4 EXAMPLE 5 3-Hydroxy-3-[ 2-phenylcyclohexyl)aminomethyl1-3 ,4-dihydro-2I-I- l ,5-benzodioxepin hydrochloride By replacing the acetoneemployed in Example 1, Step F (or alternate Step F) by an equivalentquantity of 2-phenylcyclohexanone and then following essentially thesame procedures described therein, there is obtained3-hydroxy-3-[(2-phenylcyclohexyl)aminomethyl]-3 ,4-dihydro-2H- l,S-benzodioxepin hydrochloride, mp. 21 3.52 C.

EXAMPLE 6 3 -Hydroxy-3- 2-( 3-cyclohexyl(propyl aminornethyl l-3,4-dihydro-2H-1 ,5-benzodioxepin hydrochloride By replacing the acetoneemployed in Example 1, Step F (or alternate Step F) by an equivalentquantity of cyclohexylacetone and then following essentially the sameprocedure described therein, there is obtained 3- hydroxy-3- 2-(3-cyclohexyl )propyl] arninomethyl 3,4-dihydro-2H-1 ,5 -benzodioxepinhydrochloride.

EXAMPLE 7 3-li-lydroxy-3-dimethylaminomethyl-3,4-dihydro-2l-l-1,5-benzodioxepin hydrochloride 3-I-Iydroxy-3aminomethyl-3,4-dihydro-2H- l .5- benzodioxepin (3.2 g., 0.0164 mole)from Example 1, Step E, is added to formic acid (4.3 g., 0.082 mole).Formalin (3 ml.) is added and the solution then heated on a steam bathfor 17 hours. The yellow liquid is stripped, basified with 20% sodiumhydroxide (10 ml.) and twice extracted with ether (50 ml). The etherextracts are combined and washed with water, then dried over magnesiumsulfate and calcium sulfate then evaporated yielding 3.4 g. of an oilwhich upon acidification with ethanolic-hydrogen chloride crystallizesas the hydrochloride melting at l l8-l20 C.

EXAMPLE 8 B-Hydroxy-3-methylaminomethyl-3,4-dihydro-2H- l ,5-benzodioxepin hydrochloride Step A: Preparation of3-hydroxy-3-formamidomethyl- 3 ,4-dihydro-2H- l ,5-benzodioxepin Amixture of 1.49 g. of 97% formic acid and 3.21 g. of acetic anhydride isheated in a water bath for 2 hours (internal temperature did not exceed55 C.) then cooled and added dropwise to a slurry of 5.86 g. of 3-hydroxy-3-aminomethyl-3 ,4-dihydro-2H- l ,5- benzodioxepin from Example1, Step E, in 60 ml. anhydrous ether. A gummy white solid forms whichslowly dissolves with stirring at ambient temperature overnight. Theclear liquid obtained is washed twice with water, twice with 10% sodiumcarbonate and twice with water. The ether then is evaporated affording2.5 g. of semi-solid material.

An oil, insoluble in either water or ether, is collected with the waterand then removed by shaking the mixture with chloroform. Upon strippingthe chloroform layer there is obtained 3.6 g. of3-hydroxy-3-formamidomethyl-3,4-dihydro-2I-I- l ,S-benzodioxepin in theform of a semi-solid.

Step B: Preparation of 3-hydroxy-3- methylaminomethyl-3 ,4-dihydro-2H-l,S-benzodioxepin hydrochloride 3-Hydroxy-3-formamidomethyl-3,4-dihydro-2H- l .5- benzodioxepin (5.8 g.) in 200 ml. anhydrous etheris added to lithium aluminum hydride (2.0 g.) in 40 ml. of

anhydrous ether dropwise in one hour. The mixture then is refluxed for 2hours and the excess lithium aluminum hydride then decomposed with water(5.0 ml.) followed by 10% sodium hydroxide (3.6 ml.) followed by 6.0 ml.of water. The white solid formed is filtered and the filtrate dried overmagnesium sulfate then over calcium sulfate. It is stripped affording3.8 g. of oil. The oil is acidified with 1 IN hydrochloric acid inethanol to give 3.7 g. of 3-hydroxy-3-methylaminomethyl-3,4-dihydro-ZH-1,5-benzodioxepin hydrochloride, m.p. l89-205 C. Followingseveral recrystallizations from ethanol, the product melts at 2l72l9 C.

Other benzodioxepins prepared by the methods described in Example 1 areidentified in Table I. In particular the ketone, acetone, employed inStep F of Example 1 is replaced by the carbonyl compound identified inthe following table, which, following substantially the same procedurethere described, gives the benzodioxepins I having the R substituentspecified in Table I.

Analysis Found Calcd.

M.P., C.

Empirical formula Ex. No. Carbonyl reactant CEZHQQN -11 CI OCH;

C Ha

(SCH:

CmHzrNOs Table [1 also describes additional products made by theprocedure of Example 1. The products identified here are prepared byreplacing the catechol employed in Step A of Example 1 by anequimolecular quantity of the catechol E having the R and R substituentsgiven in the table which then is carried through the proceduresdescribed in Steps A E of Example 1 to provide the3-hydroxy-3-aminomethyl compound D". Compound D thus obtained uponreaction with acetone according to the procedure described in Step F ofExample 1 provides the 3,3-disubstituted-benzodioxepin I having thesubstituents R and R given in Table II.

g ages 9 1511 20 g Ml HVH Analysis Empirical R formula CH C14H21NOa-HC1C1 CnHtsClNOaHCl H Cr4H21NO4-C4H404 The preparation of the benzodioxepinbearing an R substituent by the reaction of the 3-keto intermediate Awith a nitro-alkane, thus following the route A B D 1 is illustrated bythe examples below. It will be understood that other nitro-alkanes andother 3- oxo-benzodioxepins can be employed as starting materials aswell as other aldehydes or ketones of the type described as suitableabove. It also is possible to EXAMPLE 23 3-Hydroxy-3-(l-isopropylaminoethyl )-3 ,4-dihydro2l-ll,5-benzodioxepin hydrochlorideStep A: Preparation of 3-hydroxy-3-( l-nitroethyl)-3 ,4- dihydro-2H- 1,S-benzodioxepin To a solution of 3oxo-3,4-dihydro-2l-l-1,5-

.' benzodioxepin (9.84 g., 60 millimoles) prepared as described inExample 1, Steps A-C in anhydrous ethanol (30 ml.) is added nitro-ethane(10 ml.) and the mixture cooled to C. A solution of sodium (1.5 g., 65millimoles) in anhydrous ethanol (30 ml.) then is added dropwise withstirring at about C. Stirring is continued at this temperature for 1hour and for another hour at ambient temperature. Dry ether (60 ml.) isadded and the mixture then stirred overnight. More dry ether (60 ml.) isadded and the solid is collected after stirring the mixture for 2 hoursto give 5.73 g. of product after drying in a desiccator.

Evaporation of the mother liquors to a syrup and dilution with dry ether(ca. 50 ml.) yielded a further 5.32 g. of product.

Treatment of a suspension of the combined yield of product in dry etherwith a slight excess of acetic acid liberated3-hydroxy-3-(1-nitroethyl)-3,4-dihydro-2H- l,5-benzodioxepin which isisolated from the ethereal solution after washing the latter with waterand then drying it thoroughly first over magnesium sulfate and then overcalcium sulfate. I m, I Step B: Preparation of3-(1-aminoethyl)-3-hydroxy- 3 ,4-dihydro-2H-1 ,S-benzodioxepinhydrochloride The crude nitro compound (5.34 g., 22.3 rnillimoles)dissolved in a mixture of ethanol (30 ml.) and acetic acid (2 ml.) ishydrogenated at 45 C. and atmospheric pressure in the presence of Raneynickel (ca. 2.5 g.). On working up the product as its hydrogen chloridesalt as described in Step E of Example 1, there is obtained 3-(1-aminoethyl)-3-hydroxy-3,4-dihydro-2l-I-1 ,5- benzodioxepinhydrochloride, m.p. 178183 C. after crystallization from a mixture ofisopropanol and ether.

Analysis calculated for C H No -l-lClz (3,5377; H, 6.56; Cl, 14.43;N,5.70;

Found: C, 54.06; H, 6.58; Cl, 14.68; N, 5.79.

isopropylaminoethyl )-3,4-dihydro -2H- l ,5-benzodiox epin hydrochlorideBy replacing the 3-hydroxy-3-aminomethyl-3,4-dihydro-2H-l,5-benzodioxepin hydrochloride employed in Step F of Example1 by an equivalent quantity of 3-hydroxy-3-(l-aminoethyl)-3,4-dihydro-2H- l ,5- benzodioxepin hydrochloride andemploying the same reaction conditions called for in Example 1, Step F,there is obtained 3-hydroxy-3-( l-isopropylaminoethyD-3,4-dihydro-2H-l,5-benzodioxepin hydrochloride, m.p. 206211 C. It was purified byrecrystallization from ethanol giving a product of m.p. 2l5-7 HC Cl N CH,,NO,'HCl requires 58.43 7.71 12.32 4.87 found58.43 7.55 12.59 5.04

EXAMPLE 24 3-l-lydroxy-3-[ 1-(isopropylarnino)propyl]-3,4-dihydro-21-1-1 ,S-benzodioxepin hydrochloride Step B: Preparation of3-hydroxy-3-[ 1- (isopropylamino)propyl]-3 ,4-dihydro-2l-l- 1 ,5-benzodioxepin hydrochloride This product is prepared by the proceduredescribed in Example 1, Step F, except the 3-hydroxy-3-aminomethyl-3,4-dihydro-2H-1 ,S-benzodioxepin employed therein isreplaced by an equivalent quantity of '3-hydroxy-3-(l-aminopropyl)-3,4-dihydro-2H- 1 ,5-

benzodioxepin.

By following the procedure called for in Example 23, Step C, butemploying the carbonyl reactant identified in Table HI, there areobtained additional products I having an R substituent. Illustrativeexamples are pro- Step C: Preparation of 3-hydroxy-3-( 1- vided in thefollowing Table.

. TABL I W a H H H H O O... 0H Example 1, Step F OH Carbonyl ReactantCH-NHz-HCI Math CH-NHR H H R H H R "D" (II)! D" intermediate fromExample No. example R Carbonylreactant R 25 23 CH; 0113 CH(CHa)(C2Hi) 2623 -CH3 CH3 CH(OHa)-CH CHz- =0 D intermediate from Example No example RCarbonylreactant IR 27 24 CH2CH: $11: I CH2C=O 28 23 #0113 omen cn on 3HOCHz( J= 24 -CH CH CH 29 2 3 Cl-I(CH )CHz-0H HO CHzC=O a0 2a 4331; CH

I CH(CH )CH2 CH C=O 31 23 CH:; OH;

| CH(CH3)CH: Cl Cl CHz-C=O 32 A 4 4 A 24 CH2CH: CH3

l CH(CH3)CH, CHzC=O CH;CHO 2)2 34 23 CH3 CHa-CHO CH5 36 24 CH CH3 CH ICH(CH )CH O 0 CH1C=O CH2 CH2 O 37 23 CH3 CH: OCHK EH 0 CH2C=O CH(CH:4)CHOCH:

CH: I OCH; OCHs 3s 24 CH9CH3 CH3 I CH(CH3) (CH2)2 (CH2)2-C=O 24 CHzCH:CI[1I CI{O -CgH '23 C1I:; CH

I CII(CHa)(CH2)2- (C 2)2C=O 41 23 -CII3 CH3 I CH(CH3)CHz -0 T -CHz--C=OO H CHz-( g The following examples illustrate the preparation of the3,3-disubstituted-benzodioxepins I by forming the 3-spiro-2'-oxiranewhich when reacted with an amine gives the desired product I, that isthe route D E I illustrated in Flow Diagram I. It will be appreciatedthat anyone of the intermediate compounds D described in this disclosureas well as others falling within the scope of its definition can beemployed as starting substance and any amine of structure HNR R can besubstituted for the particular amine employed to provide the desiredproduct 1.

EXAMPLE 57 3-hydroxy-3-t.-butylaminomethyl-3 ,4-dihydro-2H-1 ,5benzodioxepin hydrochloride Step A: Preparation of3,4-dihydro-2H-l,S-benzodioxepin-3-spiro-2'-oxirane A solution of sodiumnitrite (6.9 g.; 0.1 mole) in water (50 ml.) is added slowly over aperiod of one-half hour with stirring to a solution of 3-hydroxy-3-aminomethyl-3 ,4-dihydro-2H- l ,5-benzodioxepin hydrochloride (23.17 g.;0.1 mole), in water (200 ml.) containing acetic acid (0.1 ml.) whilemaintaining the reaction mixture at a temperature between about -4 to C.When the addition is completed the reaction mixture then is allowed towarm to ambient temperature. The solid that forms is collected andwashed with a little water to yield 14.84 g. of crude product, m.p.l32-l44 C. Following recrystallization from methanol (approximately 30parts V/W) there is obtained l 1.65 g. (65.3%) of 3,4-dihydro-2l-I-l ,5-benzodioxepin-3-spiro-2-oxirane, m.p. 147l 49 C.

Analysis calculated for c u o C, 67.40; H, 5.66; O, 26.94;

Found: C, 67.46; H, 5.46; O, 27.37.

Recrystallization of the crude product of Step A from chloroform alsoprovides purified product that does not depress the melting point whentaken in admixture with the purified product of Step A.

The mother liquor remaining after the removal of the crude product inStep A is extracted with ether yielding an oil (1.3 g.) whichcrystallizes from carbon tetrachloride to afford 300 mgs. of3-hydroxy-3- hydroxymethyl-3,4-dihydro-2H-l ,S-benzodioxepin, m.p.120123 C. Recrystallization of the diol from water (6 ml.) provides 254mgs. of product, m.p. 124.5-125.5 C.

Analysis calculated for C H O Found: C, 61.16; H, 6.28.

The diol obtained as described above also exhibits ,8- adrenergicstimulating properties and therefore is useful as a bronchial dilatingagent.

Step B: Preparation of 3-hydroxy-3-t.-butylaminomethyl-3,4-dihydro-2H- l,S-benzodioxepin hydrochloride The 3,4-dihydro-2I-I- 1,S-benzodioxepin-3-spiro-2'- oxirane (1.78 g.), obtained as described inStep A, is stirred at ambient temperature with t.-butylamine (3.2 ml.)in methanol (25 ml.) for 42 hours. The solution then is evaporated to2.6 g. of oil which is separated and dissolved in ether and thenacidified with 1 IN HCl in ethanol (2.5 ml.) to give 2.0 g. of crudeproduct, m.p. l69.5-177 C. AFter recrystallization from isopropanolcontaining decolorizing charcoal there is obtained 3-hydroxy-3-t.-butylaminomethyl-3 ,4-

EXAMPLE 58 3-hydroxy-3-(2-dimethylaminoethyl)aminomethyl-3,4-

dihydro-ZH-l ,S-benzodioxepin dihydrochloride 3 ,4-Dihydro-2I-l-1,5-benzodioxepin-3-spiro-2-oxirane (3.56 g., 20 millimoles) from Example57, Step A, is stirred with 5.3 g. millimoles) of unsymmetricaldimethylethylenediamine in 50 ml. of methanol for 48 hours at 30-40 C.The solution is evaporated to remove methanol and excessdimethylethylenediamine. The residual oil is dissolved in diethyl etherand acidified with ethanolic-hydrogen chloride to give crude producthydrochloride. This product is dissolved in ethanol, treated withcharcoal, and filtered. Concentration of the filtrate and refrigerationaffords 3- hydroxy-3-(Z-dimethylaminoethyl)-aminomethyl-3,4- dihydro-2H-l ,S-benzodioxepin dihydrochloride.

The following example describes the preparation of the3-spiro-2'-oxirane E from a 3-oxobenzodioxepin A employing a sulfurylide. While the example describes the use of dimethyloxosulfoniummethylide in the preparation of the 3-spiro2'-oxirane, the desiredoxirane can also be obtained by replacing the sulfur ylide bydimethylsulfonium methylide prepared in situ by the process heretoforedescribed.

EXAMPLE 59 3 ,4-dihydro-2l-ll ,5-benzodioxepin-3-spiro-2-oxirane3-Oxo-3,4-dihydro-2II-l ,S-benzodioxepin (1.64 g.; 10 millimoles) fromExample 1, Step C, is added slowly with stirring during 15 minutes atambient temperature to a solution of dimethyloxosulfonium methylideprepared under nitrogen from 15 millimoles of sodium hydride, 15millimoles of trimethyloxosulfonium iodide, and 30 mls. of dimethylsulfoxide. The mixture is stirred for 24 hours at ambient temperatureand then 2 hours at 4550 C. The mixture is cooled and poured onto 50 g.of ice and repeatedly extracted with diethyl ether. The ethereal extractis washed with water, dried over anhydrous magnesium sulfate andevaporated. The crude product is crystallized from methanol to affordthe 3,4-dihydro-2H-l ,5-benzodioxepin-3-spiro-2'- oxirane identical withthe product prepared from 3- hydroxy-3-aminomethyl-3 ,4-dihydro-2H-1 ,5-benzodioxepin as described in Example 57, Step A.

The other 3-oxo-3,4-dihydro-2H-l ,S-benzodioxepins describedSpecifically in this disclosure or falling within the scope of thedefinition of the 3-keto compound A" can be substituted for theparticular 3-keto starting substance in Example 59 to provide thedesired 3- spiro-2-oxirane of structure E.

Additional compounds prepared by the process described in Example 57 areidentified in Table V. The products of Table V are prepared by replacingthe t.-

butylamine employed in Step B of Example 57 by an equimolecular quantityof the amine having the structure fiNR R identified in Table V and thenfollowing substantially the same procedure described in Step B.

TABLE VI-(uminuc l V o w/ 0 El tggp fi 57 OH I HNR R I Method CHNRsRs \Q5 Example No. R R

77 (CH2)2l| I--(CHz)i' 10 7s... H CHz-CH=CH2 79 H CH:C=CH2 80 H CH(CH3)2s1 H' (3H CHOH: OH

82 H ICH3 CHCH U w 33 H CH CH-CHr s4 H OH,(0H,),NH

The following examples describe the preparation of certain3,3-disubstituted-benzodioxepins having at least one substituentattached to its benzenoid moiety.

EXAMPLE 8 5 3-Hydroxy-3-isopropyla.minomethyl-7-nitro-3,4- dihydro-ZH- 1,5-benzodioxepin Hydrochloride.

Step B; Preparation of 3-hydroxy-3- isopropylaminomethyl- 7-nitro-3,4-dihydro-2H-1 ,5 benzodioxepin Hydrochloride By replacing the3-spiro-2-oxirane and the t.-butylamine employed in Step B of Example 57by equivalent quantities of 7-nitro-3,4-dihydro-2H-l,5-benzodioxepin-3-spiro-2'-oxirane and isopropylamine respectively andthen following substantially the same procedure there described, thereis obtained 3-hydroxy-3-isopropylaminomethyl-7-nitro-3,4-dihydro-2H-l ,5benzodioxepin hydrochloride.

EXAMPLE 86 3-Hydroxy-3-isopropylaminomethyl-7-amino*3,4- dihydro-ZH-l,S-benzodioxepin Hydrochloride Step A: Preparation 7' of 3-Acetoxy-3-(N-acetylisopropylaminomethyl)-7-nitro-3,4-dihydro-2H- l ,S-benzodioxepinTreatment of 3-hydroxy-3-isopropylaminomethyl-7-nitro-3,4-dihydro-2H-l,S-benzodioxepin, obtained as described in Example85, with excess acetic anhydride and heating overnight on a water bathaffords the 3- acetoxy-3-(N-acetylisopropylaminomethyl)-7-nitro- 3,4-dihydro-2H- l ,S-benzodioxepin. Step B: Preparation of3-Acetoxy-3-(N- acetylisopropylaminomethyl)-7-amino-3,4-dihydro- 2H- 1,S-benzodioxepin The 3-acetoxy-3-(N-acetylisopropylaminomethyl)-7-nitro-3,4-dihydro-2H-l,S-benzodioxepin when dissolved in ethyl acetateis reduced at low pressure over platinum with hydrogen to give3-acetoxy-3-(N- acetylisopropylarninomethyl)-7-amino-3,4-dihydro- 2H- 1,S-benzodioxepin. Step C: 3-Hydroxy-3-(isopropylaminomethyl)-7- amino-3,4-dihydro-2H-l ,5 -benzodioxepin hydrochloride3-Acetoxy-3-(N-acetylisopropylarninomethyl)-7-amino-3,4-dihydro-2H-l,S-benzodioxepin (33.6 g., 0.1 mole) is refluxedfor 10 hours with 400 ml. of methanol containing 20 g. (0.5 mole) ofsodium hydroxide. The solvent is removed at low temperature in vacuo andthe residue treated with 200 ml. of water. The mixture is extracted withdiethyl ether and the combined ether phases washed with water and driedover anhydrous magnesium sulfate. The solvent is evaporated and theproduct, 3-hydroxy-3-(isopropylaminomethyl)-7- amino-3 ,4-dihydro-2H- l,S-benzodioxepin hydrochloride isolated as the hydrochloride sale.

EXAMPLE 87 3-Hydroxy-3-isopropylaminomethyl-7-methanesulfonamido-3,4-dihydro-2H- 1 ,5- benzodioxepin HydrochlorideStep A: Preparation of 3-Acetoxy-3-(N-acetylisopropylaminomethyl)-7-methanesulfonamido- 3 ,4-dihydro-2H- l,S-benzodioxepin Methanesulfonyl chloride (0.1 mole) is added dropwiseto a stirred solution of 0.1 mole of 3-acetoxy-3-(N-acetoxyisopropylaminomethyl)-7-amino-3,4-dihydro- 2H-l,5-benzodioxepin,from Example 86 Step B, in 120 ml. of pyridine held at 10-15 C. Themixture is stirred for several hours at ambient temperature, then heatedto 90 C. for 0.5 hours, cooled, and added to an ice-water mixture. Themixture is extracted with ether, washed, dried over magnesium sulfate,and the solvent removed to give 3-acetoxy-3-(N-acetylisopropylaminomethyl)-7-methanesulfonamido- 3 ,4-dihydro-2H- 1,S-benzodioxepin. Step B: Preparation of 3-Hydroxy-3-isopropylaminomethyl-7-methanesulfonamido-3,4- dihydro-ZH- l,S-benzodioxepin 3-Acetoxy-3-(N-acetylisopropylaminomethyl)7-methanesulfonamido-3,4-dihydro-2H-l ,5-benzodioxepin (4.2 g., 10millimole) in 20 ml. methanol is treated with 2 g. (50 millimoles) ofsodium hydroxide in 20 ml.

of methanol. The mixture is refluxed for 3 hours, cooled, and dilutedwith 400 mls. of water neutralized with acid and extracted with ether.The combined ethereal solutions are washed with water, dried overanhydrous sodium sulfate, and evaporated to give 3-hydroxy-3-isopropylaminomethyl-7-methanesulfonamido-3 ,4-dihydro-2H- l,S-benzodioxepin.

, EXAMPLE 88 3-hydroxy-3-isopropylamino-7-carbethoxyamine 3,4-dihydro-ZH- 1 ,5-benzodioxepin Step A: Preparation of 3-Acetoxy-3-(N-acetylisopropyl-aminomethyl)-7-carbethoxya.mino- 3 ,4-dihydro-2H- l,S-benzodioxepin 3-Acetoxy-3N-acetylisopropylaminomethyl-7-amino-3,4-dihydro-2H-1,5-benzodioxepin (0.1 mole) from Example 86, StepB, in chloroform is treated with 0.1 1 mole of ethyl chloroformate andpyridine in chloroform. The mixture after stirring and heating in awater bath for several hours is diluted with water, extracted withether, the combined ethereal extracts washed, dried and evaporated togive 3-acetoxy-3-(N- acetylisopropylaminomethyl )-7-carbethoxyamino-3,4- dihydro-2 N-l 5 -benzodioxepin. Step B: Preparation of 3-Hydroxy-3-isopropylaminomethyl-7carbethoxyarnino-3,4- dihydro-2I-l-l,S-benzodioxepin 3-Acetoxy-3-( N acetylisopropylaminomethyl)-7-carbethoxyamino-3 ,4- dihydro-2H-l,5-benzodioxepin (4.1 g., 10millimoles) is warmed 5 hours at 40 C. with 6 ml. of concentratedhydrochloric acid and 34 ml. of ethanol. The solution is cooled, takento the basic side with sodium hydroxide, diluted with water, andextracted with diethyl ether to give3-hydroxy-3-isopropylaminomethyl-7-carbethoxyamino-3 ,4-dihydro-2l-I- l,S-benzodioxepin.

EXAMPLE 89 3,7-Dihydroxy-3-isopropylaminomethyl-3,4-dihydro- 2H- 1 ,5-benzodioxepin 3-Acetoxy-3-(N-acetylisopropylaminomethyl-7-amino-3,4-dihydro 2H-l,5-benzodioxepin from Example 86, Step B,dissolved in dilute sulfuric acid is treated with sodium nitrite inwater and the mixture heated on a water bath for 0.5 hours. The mixtureis cooled, neutralized with base, extracted with ether, the etherealextract washed, dried, and evaporated to give2,7-dihydroxy-3-isopropylaminomethyl-3,4-dihydro 2H- 1 ,Sbenzodioxepin.

EXAMPLE 90 3-Hydroxy-3-isopropylaminomethyl-7-methoxy-3,4-

dihydro-2H-l,5-benzodioxepin3,7-Dihydroxy-3isopropylaminomethyl-3,4-dihydro- 2l-l -l,5-benzodioxepin(2.53 g.; 10 millimoles) from Example 89 dissolved in 50 ml. of diethylether is left 10 hours at ambient temperature with 0.46 g. (11millimoles) of diazomethane in 25 ml. of diethyl ether. Excessdiazomethane is destroyed by addition of a few drops of acetic acid. Thesolution then is washed with water, dried over anhydrous sodium sulfate,and evaporated to dryness to give 3-hydroxy-3- 32isopropylaminomethyl-7-methoxy-3,4-dihydro-2H-1 ,5- benzodioxepin.

The products of Examples through can also be prepared followingsubstantially the same procedures described in these examples butinstead of employing the 3-spiro-2'-oxirane starting substance inExample 85, Step A, one uses an oxazolidinone which can be prepared fromproduct I by treatment with dibutyl carbonate and metallic sodium or bytreatment with phosgene. The following example illustrates thepreparation of the oxazolidinone and its use in preparing the desired7-substituted compounds of Examples 85 through 90.

EXAMPLE 91 3-Hydroxy-3-isopropylaminomethyl-7-nitro-3,4- dihydro-ZH-l ,5-benzodioxepin.

Step A: Preparation of 3'-isopropyl-3,4-c .rydro-ZH- l,5-benzodioxepin-3-spiro-5 -oxazolidin-2' one A mixture of3-hydroxy-3-isopropylaminomethyl-3,4 -dihydro-2H-l,Sbenzodioxepin (11.85g.; 50 millimoles), prepared as described in Example 1, and dibutylcarbonate (13.1 g.) with a small piece of metallic sodium is heated inan oil bath. The temperature then is slowly raised to C. with removal ofbutanol. Finally the mixture is heated between 170-200 C. with removalof excess dibutyl carbonate. The cooled reaction product is dissolved inbenzene, washed with water, dried over sodium sulfate, and the solventevaporated to give 3-isopropyl-3,4-dihydro-2H-l,5-benzodioxepin-3-spiro-5 oxazolidin-2 -one, m.p. l2l-122 C.

By replacing the 3,4-dihydro-2H-l ,S-benzodioxepin- 3-spiro-2-oxiraneemployed in Example 85, Step A, by an equivalent amount of3'-isopropyl-3,4-dihydro-2H-l,5-benzodioxepin-3-spiro-5'-oxazolidin-2'-0ne and followingsubstantially the same procedure there described, there is obtained3-isopropyl-7-nitro-3,4- dihydro-Zl-l-l ,5-benzodioxepin-3-spiro-5-0xazolidin- 2'-one, m.p. 145.5-147C.

Step C: Preparation of 3-hydroxy-3-isopropylaminomethyl-7-nitro-3,4-dihydro-2H-l ,5- benzodioxepin EXAMPLE92 3-Hydroxy-3 -isopropylaminomethyl-7-methanesulfonamide-3,4-dihydro-2H-l ,S-benzodioxepin Step A: Preparation of 3 -isopropyl-7-isopropylaminomethyl-3 ,4-dihydro-2H-l ,S-benzodioxepin-3 -spiro-5-oxazolidin-2 -one By replacing the 3-acetoxy-3-acetoxy-3-N-acetylisopropylaminomethyl-7-nitro-3,4-dihydro-2l-l- 1,5-benzodioxepinused in Example 86, Step B, by an equivalent quantity of3'-isopropyl-7-nitro-3,4-

dihydro-2H-1 ,5-benzodioxepin-3-spiro-5 '-oxazolidin- 2-one obtained asdescribed in Example 91, Step B, and then following substantially theprocedure described in Example 86, Step B, there is obtained 3'-isopropyl-7-amino-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-5'-oxazolidin-2-one. Step B: Preparation of3'-isopropyl-7-methanesulfonamido-3 ,4-dil1ydro-2H-l,5-benzodioxepin-3-spiro- 5'-oxazolidin-2-0ne 7 By reacting theoxazolidinone obtained in Step A with methanesulfonyl chloride andemploying the other reaction conditions and procedure described inExample 87, Step A, there is obtained 3'-isopropyl-7-methanesulfonamido-3,4-dihydro-2H-1 ,S-benzodioxepin-3-spiro-5-oxazolidin-2 '-one. Step C: Preparation of 3-hydr0xy-3-isopropylaminomethyl-7-methanesulfonamido-3,4- dihydro-2l-l-l,S-benzodioxepin This product is prepared by substituting theoxazolidinone compound of. Step B above for that employed in Example 91Step C, and following essentially the same reaction there described.

EXAMPLE 93 3-l-lydroxy-3-isopropylaminomethyl-7- carbethoxyamino-3,4-dihydro-2H-l ,5 -benzodioxepin Step A: Preparation of3'-isopropyl-7-carbethoxyamino-dihydro-2H-l ,S-benzodioxepin-3-spiro-5-oxazolidin-2'-one By replacing the 3-acetoxy-3N- acetylisopropylamino-3,4-dihydro-2H-1 ,S-benzodioxepin reactant in Example 88, Step A, by the3'- isopropyl-b 7-amino-3,4-dihydro-2H1,S-benzodioxepin-3-spiro-5-oxazolidin-2'-one, prepared as described inExample 92, Step A, and then following substantially the same proceduredescribed in Example 88, Step A, there is obtained3'-isopropyl-7-carbethoxyamino-3 ,4-dihydro-2l-ll,5-benzodioxepin-3-spiro-5 oxazolidin-2-one. Step B: Preparation of3-hydroxy-3- isopropylaminomethyl-7-carbethoxyamino-3,4- dihydro-ZH-l,5-benzodioxepin The oxazolidinone from Step A above is refluxed inethanol containing anhydrous hydrogen chloride. The solution isneutralized, evaporated to a small volume, diluted with water andextracted with ether. The dried ethereal solution is evaporated to givethe desired product.

EXAMPLE 94 3 ,7-Dihydroxy-3-isopropylaminomethyl-3 ,4-dihydro- 2H- 1 ,5-benzodioxepin Step A: Preparation of 3'-isopropyl-7-hydroxy-3,4-dihydro-2l-l-l ,5-benzodioxepin-3-spiro-5 -oxazolidin- 2-one Thisproduct is prepared by following the procedure and employing thereactants and reaction conditions described in Example 89 except the3-acetoxy-3-N- acetylisopropylaminomethyl-7-amino-3,4-dihydro-2H-l,5-benzodioxepin there employed is replaced by the oxazolidinoneobtained as described in Example 92, Step A.

Step B: Preparation of 3,7-dihydroxy-3- isopropylaminomethyl-3,4-dihydro-2l-l-l ,S-benzodio xepin This product is prepared bysubstituting the oxazolidine compound of Step above for that employed inExample 91, Step .C, and following essentially the I same reaction theredescribed.

EXAMPLE 95 3-l-lydroxy-3-isopropylaminomethyl-7-methoxy-3,4-dihydro-2l-ll ,S-benzodioxepin Step A: Preparation of3-isopropyl-7-methoxy-3,4- dihydro-ZH- l ,5-benzodioxepin-3-spiro-5'-oxazolidin-' 2-one This compound is prepared by employing the samereactants, reaction conditions and procedure outlined in Example 90except the 3,7-dihydroxy-3- isopropylaminomethyl-3 ,4-dihydro-2H-l,S-benzodioxepin is replaced by an equivalentquantity of 3'isopropyl-7-hydroxy-3 ,4-dihydro-2H- l,S-benzodioxepin-3-spiro-5'-oxazolidin-2'-one from 94, Step A. Step B.Preparation of 3-hydroxy-3-isopropylaminomethyl-7-methoxy-3,4-dihydro-2H- 1 ,5- benzodioxepin Thisproduct is prepared by substituting the oxazolidinone compound of Step Aabove for that employed in Example 91 Step C, and following essentiallythe same reaction there described.

EXAMPLE 96 3,6-Dihydroxy-3-isopropylaminomethyl-3,4-dihydro- 2H-1 ,5-benzodioxepin Hydrochloride Step A: Preparation of2-methoxy-2-methyl-4-hydroxyl ,3-benzodioxole A mixture of pyrogallol(25.2 g., 0.2 mole) and trimethyl orthoacetate (26.4 g., 0.22 mole) istreated with one drop of concentrated sulfuric acid and the reactionmixture then stirred under nitrogen in an oil bath at l03-l05 C.Methanol formed in the reaction is distilled up a short column andcollected. After 1 hour, more trimethyl orthoacetate (2 g., 0.016 mole)and another drop of sulfuric acid are added and the temperature of theoil bath raised to l08-l 10 C. for a further hour. Methanol (9.6 ml.) iscollected. On cooling, the dark brown oil crystallizes and is dissolvedin ether ml.), the ethereal solution is washed with 2 percent sodiumcarbonate solution (50 ml.) and then with saturated sodium chloridesolution. Evaporation of the dried ethereal solution yields 31.2 g. of apale yellow solid. The crude product is dissolved in boiling carbontetrachloride (280 ml.) and some solid (mainly pyrogallol) is removed byfiltration. On cooling, the solution yields 24.24 g. (66.6%) of2-methoxy-2- methyl-4-hydroxyl ,3-benzodioxole, m.p. l06-l 09 C. Uponfurther recrystallization of the compound from carbon tetrachloride,with treatment with charcoal and activated alumina, the product melts atll4.5l 15.5 C.

Analysis calculated for C H Found: C, 59.70; H, 5.85. Step B:Preparation of 2-Methoxy-2-methyl-4- benzyloxy-l ,3-benzodioxole To asuspension of sodium hydride (2.4 g., 0.1 mole) in freshly distilledhexamethyl-phosphoramide (24 ml.) is added dropwise with poured underdry nitrogen a solution of 2-methoxy-2-methyl-4-hydroxyl ,3-benzodioxole (18.2 g., 0.1 mole) in hexamethylphosphoramide (36 ml.) andstirring is continued at ambient temperature until hydrogen evolutionementially ceases. Benzyl chloride (12.65 g., 0.l

mole) is added and the mixture stirred at 75-80 C. for 5 hours. Themixture then is poured onto ice and adjusted to ca. pH 6 with aceticacid. The product is extracted with ether, and the ethereal solutionwashed with 2 percent sodium carbonate solution (50 ml.) and then withsaturated sodium chloride solution. After drying over magnesium sulphateand then calcium sulfate, the ethereal solution is evaporated to give 2-methoxy- 2-methyl-4-benzyloxyl ,3-benzodioxole which can be crystallizedfrom di-isopropyl ether.

Step C: preparation of S-benzyloxy catechol A mixture 2-methoxy-2-methyl-4-benzyloxy-1,3- benzodioxale 12.6 g., 0.05 mole),methanol (210 ml.) and 5N hydrochloric acid (210 m1.) is stirred underreflux in an atmosphere of nitrogen for 10 hours. Most of the methanolis distilled off under vacuum and the product then extracted with ether.The ethereal solution is washed with water, dried over magnesium sulfatefollowed by calcium sulfate and evaporated to dryness to yield the crude3-benzyloxy-catechol which can be recrystallized from di-isopropylether.

Step D: Preparation of 3-amino-4-cyano-6-benzyloxy- 3 ,4-dihydro-2H- l,S-benzodioxepin By replacing catechol employed in Step A of Example lby an equivalent quantity of 3-benzyloxycatechol and followingsubstantially the same procedures described in Steps A and B of Example1 there are obtained sequentiallyl,2-di(cyanomethoxy)-3-benzyloxybenzene and then3-amino-4-cyano-6-benzyloxy-3,4- dihydro-2H-1,5-benzodioxepin and/or the9-benzyloxy isomer.

Step E: Preparation of 3,6-dihydroxy-3-isopropylaminomethyl-3,4-dihydro-2H-2,5-benzodioxepin hydrochloride The3-amino-4-cyano6-benzy1oxy-3,4-dihydro-2l-l- 1,5-benzodioxepin and/orits 9-benzyloxy isomer is converted to3-oxo-6-benzyloxy-3,4-dihydro-2H-l,5- benzodioxepin by the proceduredescribed in Example 1, Step C, and the 3-keto compound then reactedwith potassium cyanide by either the process of Step D of Example 1 orthe alternative procedure there described to provide3-hydroxy-3-cyano-6-benzyloxy-3,4- dihydro-2H-l,5-benzodioxepin. Thisproduct then is reduced with lithium aluminum hydride by the methodoutlined in the alternate of Step E, Example 1, to give3-hydroxy-3-aminomethyl-6-benzyloxy-3,4-dihydro- 2H-1,5-benzodioxepinwhich when reacted with acetone and then reduced by the process of StepF, Example there is obtained 3,6 dihydroxy- 3 isopropylaminomethyl-3,4-dihydro-2 -dihydro-2 1,5 benxodioxepin hydrochloride.

Additional 3,3-disubstituted-benzodioxepins having at least onesubstituent attached to the benzenoid moiety that can be prepared fromthe appropriate catechol by any of the major routes illustrated in FlowDiagram 11 followed by any of the procedures illustrated in Flow Diagram1 are identified in the following Table. For convenience the catecholsidentified in Table VII are converted to the 3-oxo-benzodioxepin bysubstantially the same methods described in Example 1, Steps A through C(that is route E c F G A in Flow Diagram 11). The other route (that is EF r G "7 A) described in Examples 108 and 109 could have been employedto provide the 3-oxo -benzodioxepin A and the following table is to beunderstood as applying to this route as well. Also, for convenience theend products 1 are prepared by the procedures described in Examples 1,Steps D through F, Example 23 or Example 57, as indicated in the table(that is route A jC D I; A B D I, and A C D E 1) although the othermodifications illustrated in Flow Diagram 1 and in the Examples couldequally be employed. Step A: Preparation of1.2-bis-carbomethoxymethoxybenzene (or 1.2-benzene-bis methyl glycolate)Methyl bromoacetate (57 g.) is added portionwise to a mixture ofcatechol (24 g), potassium carbonate (62 g.), potassium iodide (3 g.)and acetone (500 ml.). The reaction gradually warmed up and aprecipitate formed. The reaction mixture then was stirred overnight atambient temperature and the precipitated substance removed byfiltration. The acetone solution was distilled to remove the acetonewhereupon an oily residue was obtained which was crystallized frommethanol yielding 27 g. of 1,2-bis-carbomethoxymethoxybenzene.

Step B: Preparation of 3- 0xo-4-carbomethoxy'-3,4- dihydro-2H1,5-benzodioxepin.

Potassium t.-butoxide (15.8 g dissolved in is added dropwise over a 45minute period to l,2-bis-caromethoxymethoxybenzene (18.3 g.) in DMSO (30m1.) under an atmosphere of nitrogen. The mixture then is stirred 3hours at ambient temperature and a mixture of acetic acid 16 ml.) andwater (200 ml.) is added. The reaction mixture is extracted withbenzene, the powdery material removed by filtration and the benzene thendried over magnesium sulfate and the benzene then evaporated leaving3-oxo-4-carbomethoxy-3,4-dihydro-2H-1,5-benzodioxepin that is used inthe following step without purification. Step C: Preparation of3-oxo-3,4-dihydro-2H-l ,5- benzodioxepin.

3-Oxo-4 carbomethoxy-3,4-dihydro-2H- l ,5- benzodioxepin (110 g.) isadded to a mixture of methanol (210 ml), concentrated hydrochloric acid(50 m1.) and water ml.) and the mixture then is refluxed for 18 hours.The product is extracted with ether, and the ether extract washed withfour 50 ml. portions of sodium bicarbonate solution, then twice with 50ml. portions of water. After drying the washed ether extract overmagnesium sulfate and evaporation to remove the solvent there isobtained 3-oxo-3,4- dihydro-ZH- 1 ,5-benzodioxepin. Step D: Preparationof 3-hydroxy-3- isopropylaminomethyl-3,4-dihydro-2l-1- 1,S-benzodioxepin hydrochloride The3-oxo-3,4-dihydro-2H-l,S-benzodioxepin is converted to the desired3-hydroxy-3- isopropylaminomethyl-3,4-dihydro-2H-l ,S-benzodioxepinhydrochloride by the procedures described in Example 1.

V STABLE vrr 1 i R: r

OH EX'MHDIB 1 See Table for on =0 R OH Steps AC Method R1 Method B,CHNHRO R0 R R H H R H H 1E IA!) III Method for A)I Ex.No. R R1 X R4 R3 REx.No. Stop 07 H (CHmC- H H H CH(O 1)z 1 D-F 0s H (OH )3C OH; H HCH(GH3)2 7 A43 00. .H (CH3):C (0110:0- H C 0H(0H1 2 123 o 100.-.. II(CHa)zClI- (CHO2CH H II C(CHa)a 57 A-B 101.. (CH3);CII- 1r (CH:)zCII H HCH(CH3) 1 D-F 102. (CH3)2CII II H OH: H (2H3 I 23 1 -0 CHCH2 103 II (Ca)2 H H H C(C a): 57 A-B 104 C1I30 H II CHCH3 H (3H3 24 A-B CHCHz-OH 105OH: H H H f -CH(CH0)1 12a 0 106 "H a H H H Ha): 51 11-13 107...... H N02H H H CH3 57 A-B (!IHCHZIII EXAMPLE 109 By following substantially thesame procedure 2-(Z-Pyridyl)-3-hydroxy-3-isopropylaminomethyl-3,4- 4

dihydro-ZH- l ,S-benzodioxepin hydrochloride.

Step A: Preparation of 2-( 2-Pyridyl)-2-(2-carboxymethoxyphenoxy)-aceticacid.

A mixture of 2-hydroxyphenoxy acetic acid (16.8 g. 0.1 mole) and 80 ml.of 5N aqueous sodium hydroxide (0.4 mole) is stirred until solution iseffected, then the solution treated with 2-bromo-2-(2-pyridyl)-aceticacid (21.6 g. 0.1 mole), and refluxed for twenty hours. The cooledsolution is taken to neutrality and the diacid crystallized from benzeneto give 2-( 2-pyridyl)-2-(carboxymethoxyphenoxy)-acetic acid.

Step B: Preparation of methyl2-(2-pyridyl)-2-(2-carbomethoxymethoxyphenoxy)-acetate.

A solution of the above diacid (30.3 g. 0.1 mole) ptoluenesulfonic acid3 g. and 300 mls. of methanol is refluxed for 24 hours and the solventthen removed, and replaced by diethyl ether. The ethereal solution iswashed with water, 5 percent sodium bicarbonate, then again with water,dried over anhydrous sodium sulfate, and evaporated to give methyl2-(2-pyridyl)-2-(2-carbomethoxymethoxyphenoxy) acetate.

Step C: Preparation of 2-( 2-pyridyl)-3-oxo-3,4- dihydro-ZI-I- l,S-benzodioxepin.

0 described in Example 108, Steps B and C, but substituting methyl2-(2-pyridyl)-2-(2-carbomethoxymethoxyphenoxy)-acetate for the1,2-bis-(carbomethoxymethoxy)benzene there is obtained sequentially 2-(2- pyridyl )-3-oxo-4-carbomethoxy-3,4-dihydro-2H-l ,5- benzodioxepin andthen 2-(2-pyridyl)-3-oxo-3,4- dihydro-ZH- l ,5-benzodioxepin.

Step D: Preparation of 2-(2-pyridly)-3-hydroxy-3-isopropylaminomethyl-3,4-dihydro-2H- l ,5-benzodioxpin hydrochloride.

This product is prepared by replacing the 3 -oxobenzodioxepin employedin Example 1, Step D, by an equivalent quantity of2-(2-pyridyl)-3-oxo-3,4- dihydro-2I-I-1,5-benzodioxepin and thenemploying the other reactants and reaction conditions of Steps D throughFof Example 1. I

Other compounds exemplary of those that can be prepared by the processescalled for in Example 109 are identified in Table VIII. These2-substitutedbenzodioxepins are made by replacing the 2-bromo-2-(2-pyridyl)-acetic acid employed in Step A of Example 109 by anequivalent quantity of the haloacetic acid identified in the followingtable and then following the procedures of Example 109 Steps A and B,Example 108, Steps B and C and finally Steps D through F of Example l

2. A 3,3-disubstituted-benzodioxepin as claimed in claim 1 whereinR,R1,X,X1,R2,R3 and R5 each represent hydrogen, R4 represents loweralkyl and R6 has the meaning assigned in claim
 3. A3,3-disubstituted-benzodioxepin as claimed in claim 1 whereinR,R1,X,X1,R2,R3 and R5 each represent hydrogen, R4 represents loweralkyl and R6 represents lower alkyl.
 4. A3,3-disubstituted-benzodioxepin as claimed in claim 1 whereinR,R1,X,X1,R2,R3 and R5 each represent hydrogen, R4 represents methyl andR6 represents lower alkyl.
 5. A 3,3-disubstituted-benzodioxepin asclaimed in claim 1 wherein R,R1,X,X1,R2,R3 and R5 each representhydrogen, R4 represents ethyl and R6 represents lower alkyl.
 6. A3,3-disubstituted-benzodioxepin as claimed in claim 1 whereinR,R1,X,X1,R2,R3 and R5 each represent hydrogen, R4 represents methyl andR6 represents isopropyl.
 7. A 3,3-disubstituted-benzodioxepin as claimedin claim 1 wherein R,R1,X,X1,R2,R3 and R5 each represent hydrogen, R4represents ethyl and R6 represents isopropyl.
 8. A3,3-disubstituted-benzodioxepin as claimed in claim 1 whereinR,R1,X,X1R3,R4, and R5 each represent hydrogen and R6 has the meaningassigned in claim
 1. 9. A 3,3-disubstituted-benzodioxepin as claimed inclaim 8 wherein R6 represents (hydroxy-phenyl)-lower alkyl.
 10. A3,3-disubstituted-benzodioxepin as claimed in claim 8 wherein R6represents phenyl-lower alkyl.
 11. A 3,3-disubstituted-benzodioxepin asclaimed in claim 1 wherein R,R1,X,X1,R3 and R5 each represent hydrogenand R2,R4 and R6 have the meaning assigned to each in claim
 1. 12. A3,3-disubstituted-benzodioxepin as claimed in claim 1 wherein R, R1, X,X1, and R3 each separately represent hydrogen and R2, R4, R5 and R6 eachhave the meaning assigned in claim
 1. 13. A3,3-disubstituted-benzodioxepin as claimed in claim 1 whereIn R, R1, X,X1, R2, R3 and R4 each represent hydrogen and R5 and R6 have the meaningassigned to each of them in claim
 1. 14. A3,3-disubstituted-benzodioxepin as claimed in claim 1 wherein R, R1, X,X1, R3, R4 and R5 each represent hydrogen, R2 is lower alkyl and R6 islower alkyl.
 15. A 3,3-disubstituted-benzodioxepin as claimed in claim 1wherein R, X, X1, R2, R3, R4 and R5 each represent hydrogen, R1 has themeaning assigned to it in claim 1 and R6 is lower alkyl.
 16. A3,3-disubstituted-benzodioxepin having the structure
 17. A3,3-disubstituted-benzodioxepin as claimed in claim 16 wherein R6represents isopropyl.
 18. A 3,3-disubstituted-benzodioxepin as claimedin claim 16 wherein R6 represents t.butyl. 19.2-Methyl-3-hydroxy-3-tert-butylaminomethyl-3,4-dihydro-2H-1,5-benzodioxepin. 20.3-Hydroxy-3-sec.-butylaminomethyl-3,4-dihydro-2H-1,5-benzodioxepin. 21.3-Hydroxy-3-3,4-dihydro-2H-1,5-benzodioxepin. 22.3-Hydroxy-3-(3-phenyl-2-propylamino-methyl)-3,4-dihydro-2H-1,5-benzodioxepin. 23.3-Hydroxy-3-ethylaminomethyl-3,4-dihydro-2H-1,5-benzodioxepin.